| Abstract: |
BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.) Copyright © 2015 Massachusetts Medical Society. |
| Keywords: |
signal transduction; adolescent; adult; controlled study; protein expression; aged; middle aged; gene cluster; gene mutation; major clinical study; promoter region; sequence analysis; genetics; mutation; mortality; outcome assessment; glioma; cancer grading; accuracy; chromosome 1; chromosome 19; metabolism; microrna; cluster analysis; gene expression; proportional hazards models; genetic association; gene function; protein p53; dna methylation; carcinogenesis; genome analysis; oncogene; tumor suppressor gene; proportional hazards model; dna; messenger rna; gene identification; glioblastoma; dna, neoplasm; telomerase reverse transcriptase; chromosomes, human, pair 19; dna sequence; gene inactivation; kaplan meier method; gene dosage; chromosomes, human, pair 1; genes, p53; notch1 receptor; sequence analysis, dna; molecular pathology; disease activity; kaplan-meier estimate; exome; neoplasm grading; atrx gene; tert gene; humans; human; male; female; priority journal; article; idh gene; cic gene; fubp1 gene; notch1 gene
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